The RET/PTC oncogene, a rearranged form of the RET receptor tyrosine kinase, is believed to play an important role in the pathogenesis of papillary thyroid cancer (PTC), in particular in pediatric patients and those with prior radiation exposure. The long-term goal of the proposed project is to understand the underlying mechanisms of the effects of RET/PTC oncogene on tumorigenesis, progression, and radioiodine therapy of human PTC. In this proposal, three specific aims are identified. In Aim 1, we will investigate the onset of RET/PTC1 in thyroid tumorigenesis and the requirement of RET/PTC1 in tumor maintenance/ progression. We are generating doxycycline-inducible thyroid-targeted RET/PTC1-luciferase bi-transgenic mice; such that RET/PTC1 expression can be modulated by administration of doxycycline and thyroid tumor formation can be non-invasively monitored by MS imaging. We hypothesize that RET/PTC mediated tumor formation is modulated by the intrinsic proliferation capacity of thyrocytes at the time of RET/PTC activation. In Aim 2, we will delineate the underlying mechanisms of NIS modulation by phosphorylation and protein complex formation. We have identified four in vivo phosphorylation sites in NIS and have demonstrated possible significance of these four phosphorylation sites in modulating NIS activity. We will further characterize the functional significance of these four phosphorylation sites and identify signaling/kinases that modulate these phosphorylation sites. In addition, we will examine whether differences in NIS phosphorylation and NIS protein complexes contributes to the discordance between NIS cell surface levels and NIS activity. In Aim 3, we will screen for agents that selectively increase radioiodine accumulation in thyroid tumors using a pre-clinical animal model and examine RET/PTC1 effects on radionuclide uptake and retention in the thyroid of live animals.